Pneumococcus is a major respiratory tract pathogen and causes infections in children and adults, such as invasive pneumococcal disease (IPD) including meningitis and sepsis, and community-acquired pneumonia. The antigens of the current pneumococcal vaccines are capsular polysaccharides, which determine the serotypes of pneumococci, and so far as known, there are at least 93 serotypes.
A heptavalent pneumococcal conjugate vaccine (PCV7), which is composed of a non-toxic diphtheria toxin (CRM197) bound to polysaccharide antigens, was introduced as a pediatric vaccine in the U.S.A. in 2000. After the introduction of PCV7, the incidence of IPD caused by the seven serotypes covered by this vaccine was clearly reduced, but an increase in the incidence of pediatric and adult IPD caused by nonvaccine serotypes such as 19A became a problem. For this reason, a 13-valent pneumococcal conjugate vaccine (PCV13), which is composed of PCV7 and additional capsular polysaccharide antigens of six other serotypes, was introduced in 2010 and already approved for children and adults in the U.S.A.
However, according to a large-scale survey by Non Patent Literature 1, only 60% of pediatric invasive pneumococcal isolates collected in Alabama, U.S.A. between 2002 and 2010 (before the introduction of PCV13) had serotypes covered by PCV13. The remaining 40% of these isolates included 17 serotypes that were not covered by PCV13 (Non Patent Literature 1). In Japan, publicly-aided pediatric PCV7 vaccination was started in 2011, but it was reported in 2012 that the incidence of IPD caused by nonvaccine serotypes was increased as is the case in the U.S.A. (Non Patent Literature 2). Thus, it is unreal to continue complementing the current vaccines with capsular polysaccharide antigens of nonvaccine serotypes, and this implies the limitations of the current pneumococcal vaccines based on capsular polysaccharides.
Recently, pneumococcal surface protein A (hereinafter referred to as “PspA”), which is a pneumococcal surface protein antigen, has drawn attention as a novel pneumococcal vaccine antigen to compensate for the above-described drawback of the current pneumococcal vaccines. PspA has a structure composed of several domains shown in FIG. 1, and the α-helical region and the proline-rich region of PspA are known to have antigen epitopes for recognition by protective antibodies against pneumococcal infection (Non Patent Literature 3 and 4). According to the gene sequences of the antigen epitope regions, PspA is roughly grouped into three families including six subgroups called clades. Regarding the PspA family distribution, families 1 and 2 account for 98% or more of pneumococcal clinical isolates (Non Patent Literature 5). PspA is known to serve as a virulence factor to inhibit the deposition of complement C3 onto pneumococcal cells (Non Patent Literature 6), and in contrast, an anti-PspA specific antibody is known to exert protective effect against pneumococcal infection by antagonizing the inhibitory action of PspA against complement deposition (Non Patent Literature 7 and 8). This infection protective effect is reportedly exerted also by antibodies that cross-recognize different families of PspAs (Non Patent Literature 9). Due to the diversity of the cross-reactive immunogenicity among different PspAs (Non Patent Literature 10 and 11), appropriate selection of a combination of clades belonging to families 1 and 2 for broader cross-reactive immunogenicity is important in the development of PspA-based vaccines.
The usefulness of PspA proteins as an immunogenic component of vaccines against pneumococcal infection is described, for example, in Patent Literature 1 and 2.
Non Patent Literature 12 describes the examination on the vaccine effects of a fusion protein of a family 1, clade 1 PspA and a family 2, clade 4 PspA and a fusion protein of a family 1, clade 1 PspA and a family 2, clade 3 PspA. Non Patent Literature 13 describes the examination on the vaccine effect of a fusion protein of a family 1, clade 2 PspA and a family 2, clade 4 PspA. However, these PspA-based fusion proteins described in the two cited references have not been evaluated for the vaccine effects on pneumococcal stains expressing PspAs of clades 5 and 6, or for the vaccine effects against a wide range of pneumococcal clinical isolates, and also there has been no report that these fusion proteins are already in practical use.